FGF/FGFR2 signaling regulates the generation and correct positioning of Bergmann glia cells in the developing mouse cerebellum

PLoS One. 2014 Jul 1;9(7):e101124. doi: 10.1371/journal.pone.0101124. eCollection 2014.

Abstract

The normal cellular organization and layering of the vertebrate cerebellum is established during embryonic and early postnatal development by the interplay of a complex array of genetic and signaling pathways. Disruption of these processes and of the proper layering of the cerebellum usually leads to ataxic behaviors. Here, we analyzed the relative contribution of Fibroblast growth factor receptor 2 (FGFR2)-mediated signaling to cerebellar development in conditional Fgfr2 single mutant mice. We show that during embryonic mouse development, Fgfr2 expression is higher in the anterior cerebellar primordium and excluded from the proliferative ventricular neuroepithelium. Consistent with this finding, conditional Fgfr2 single mutant mice display the most prominent defects in the anterior lobules of the adult cerebellum. In this context, FGFR2-mediated signaling is required for the proper generation of Bergmann glia cells and the correct positioning of these cells within the Purkinje cell layer, and for cell survival in the developing cerebellar primordium. Using cerebellar microexplant cultures treated with an FGFR agonist (FGF9) or antagonist (SU5402), we also show that FGF9/FGFR-mediated signaling inhibits the outward migration of radial glia and Bergmann glia precursors and cells, and might thus act as a positioning cue for these cells. Altogether, our findings reveal the specific functions of the FGFR2-mediated signaling pathway in the generation and positioning of Bergmann glia cells during cerebellar development in the mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival
  • Cerebellum / cytology
  • Cerebellum / embryology
  • Cerebellum / metabolism*
  • Fibroblast Growth Factors / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuroglia / cytology
  • Neuroglia / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
  • Signal Transduction*

Substances

  • Fibroblast Growth Factors
  • Fgfr2 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 2

Grants and funding

This work was supported by the EU grant 'Systems Biology of Stem Cells and Reprogramming' (SyBoSS [FP7-Health-F4-2010-242129]) and by the Helmholtz Alliance HelMA- Helmholtz Alliance for Mental Health in an Ageing Society, through the Initiative and Network Fund of the Helmholtz Association. Part of this work was performed within the project framework of the German national genome research funded by the Bundesministerium für Bildung und Forschung with grant number FKZ01GS0858 in the DiGtoP consortium and the BMBF funded grant 01GN1009C in the network 'Neurogenesis from brain and skin cells'. All responsibilities of this publication are due to the author(s). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.